Rheumatic diseases are characterized by inflammation and loss of function in one or more connecting or supporting structures of the body. Those structures especially affected are joints, tendons, ligaments, bones and muscles and in some cases internal organs. Some rheumatic diseases are classified as connective tissue disorders and include osteoarthritis, fibromyalgia, spondyloarthropathies, gout, polymyositis, bursitis and tendonitis. Other rheumatic diseases are classified as automimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, scleroderma, and psoriatic arthritis. An estimated 45 million people in the United States have arthritis or other rheumatic conditions and rheumatic diseases are the leading cause of disability among adults age 65 and older. While the pathogenesis of the diseases may vary, their characteristic inflammatory symptoms often share common inflammatory mediators.
Rheumatoid arthritis (RA) is a rheumatic disease characterized by persistent synovial tissue inflammation. In time, this persistent inflammation can lead to bone erosion, destruction of cartilage, and complete loss of joint integrity. Eventually, multiple organs may be affected (Rindfleish et al. American Family Physician (2005), 72(6):103746). Joint damage is initiated by proliferation of synovial macrophages and fibroblasts after a triggering incident, possibly autoimmune or infectious. This is followed by infiltration of the perivascular regions by lymphocytes and endothelial cell proliferation. Over time, inflamed synovial tissue begins to grow irregularly, forming invasive pannus tissue. The pannus invades and destroys cartilage and bone. Multiple cytokines, interleukins, proteinases, and growth factors are released causing further joint destruction and the development of systemic conditions (Ruddy et al. eds. Kelly's Textbook of Rheumatology. 7th ed. Philadelphia: W.B. Saunders, 2005:996-1042).
The symptoms of rheumatoid arthritis present as pain and stiffness in multiple joints. Symptoms can emerge over weeks and are often accompanied by anorexia, weakness, or fatigue. Joints most commonly affected are those with the highest ratio of synovium to articular cartilage, including the wrists and the proximal interphalangeal and metacarpophalangeal joints (Ruddy et al. eds. Kelly's Textbook of Rheumatology 7th ed. Philadelphia: W.B. Saunders, 2005:996-1042). Destruction of joints can begin within a few weeks of symptom onset. Early diagnosis is imperative as early treatment is effective in slowing disease progression. However, there are currently no diagnostic tests that can conclusively confirm rheumatoid arthritis.
The management of rheumatoid arthritis typically consists of medication and non-medication based treatments. Treatments aimed at reversing the course of the disease have so far been largely unsuccessful. Instead, therapeutic goals typically focus on preservation of function and quality of life, minimization of pain and inflammation, joint protection, and control of systemic complications (Harris, (2005) and American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, Arthritis Rheum (2002), 46:328-46). A typical treatment regimen includes administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for control of pain, with selective use of oral and intra-articular glucocorticosteroids, and initiation of one or more disease-modifying anti-rheumatic drugs (DMARDs). DMARDs commonly used include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. In a recent reversal of therapeutic paradigms, early and aggressive treatment with one or more DMARDs is now favored. While this more intensive regime has shown promise when treated early, only a fraction of patients achieve the ideal goal of halted progression and/or elimination of clinical activity (Machold et al., Arthritis Research & Therapy (2006), 8:1-6). A number of new biologics are also available for treating rheumatoid arthritis including infliximab (Remicade®), a chimeric tumor necrosis factor alpha (TNF-α) specific antibody; etanercept (Enbrel®), a soluble dimerized human p72 receptor/Fc fusion protein that competitively binds TNF-α; and anakinra, an interleukin-1 receptor blocker. While this new class of anti-rheumatic drugs has shown promise as a substitute or complementary form of treatment, infectious complications have been observed following treatment (Imaizumi et al., Intern. Med. (2006), 48(10):685-88).
There is an increasing appreciation for the role that angiogenesis plays in RA initiation and progression (Koch, Ann Rheum Dis (2000), 59(Suppl. I):i65-i71 and Veale et al., Best Practice & Research Clinical Rheumatology (2006), 20(5):941-47). Chronic inflammation and angiogenesis are codependent, with the proliferation, migration and recruitment of tissue and inflammatory cells capable, through direct and indirect means, of stimulating angiogenesis. Likewise, angiogenesis contributes to inflammatory pathology through the creation of new blood vessels that sustain the chronic inflammatory state by transporting inflammatory cells and supplying nutrients and oxygen to the inflamed tissue (Jackson et al., FASEB Journal, (1997), 11:457-65). Several angiogenic inducers have been identified as having a role in RA, including FGF2; VEGF; TGFβ; TNFα; chemokines, such as IL8, IL18, and IL1; soluble adhesion molecules, such as E-selectin and soluble VCAM-1; glycoconjugates, such as the soluble 4A11 antigen, soluble CD 146 and the angiopoietin-Tie system (Koch, Ann. Rheum. Dis. (2003), 62(Suppl. II):ii60-ii67).
Joints affected by RA have been shown to be hypoxic. Contributing factors to hypoxia in RA joints include the high metabolic demand of inflamed synovial tissue and the rapid rate of synovial proliferation which quickly outgrows the supporting vasculature (Taylor et al., Current Opinion in Rheumatology (2005), 17:293-98). Tissue hypoxia in a rheumatoid joint results in increased VEGF mRNA stability and enhanced VEFG gene expression through the binding of hypoxia inducible factor-1 (HIF-1) (Richard et al., Biochem Biophys Res Commun. (1999), 266:718-22). HIF-1, which is made up of HIF-1α and hydroxycarbon nuclear transclocator (ARNT), controls many transcription responses to hypoxia by binding the hypoxia response elements in target genes like the VEGF gene (Jones et al., Cancer J Sci Am. (1998), 4:209-17). HIF-1 is overexpressed in the synovial lining and stromal cells of RA patients relative to synovial tissues from individuals without RA (Hollander et al., Arthritis Rheum. (2001), 44:1540-44 and Giatromanolaki et al., Arthritis Res Ther. (2003), 5:R193-R201). VEGF is also intimately linked with the processes of immune regulation as a number of cytokines and growth factors regulate its expression in different cell types including interleukin 1β, TGFβ, FGF-2, and TNFα. Studies have shown a synergestic interaction between growth factors and hypoxia in VEGF induction (Brenchley, Ann Rheu Dis (2001), 60:iii71-iii74).
Several compounds have been used to inhibit angiogenesis. One such compound is 2-methoxyestradiol (2ME2). 2ME2 is a naturally occurring derivative of estradiol and has been shown to be an orally active, well-tolerated, small molecule that possess anti-proliferative and anti-angiogenic activity (Pribluda et al., Cancer Metastasis Rev. (2000), 19(1-2):173-9). 2ME2 has low affinity for estrogen receptors, α and β, and its anti-proliferative activity is independent of the interaction with those receptors (LaVallee et al. Cancer Research (2002), 62(13):3691-7). Several mechanisms have been proposed for 2ME2 activity, including those mediated by its ability to bind to the colchicines binding site of tubulin (Cushman et al., 1995; D'Amato et al., 1994), destabilization of microtubules and inhibition of HIF-1α nuclear accumulation (Mabjeesh et al., Cancer Cell, (2003) 3:363-75), induction of the extrinsic apoptotic pathway through upregulation of Death Receptor 5 (LaVallee et al., Cancer Research (2003), 63(2):469-75) and induction of the intrinsic apoptotic pathway, potentially through the inhibition of superoxide dismutase enzymatic activity (Huang et al., Trends Cell Biology (2001), 11(8):343-8).
What is needed are methods and compositions capable of stopping progression and/or reversing the progression of both early and late stage rheumatic diseases without unwanted or undesirable complications or side effects.